RECOVER 2.0 Worksheet

QUESTION ID: Newborn-13

PICO Question:
In newborn dogs and cats receiving chest compressions (P), how does other compression to ventilation ratios (e.g., 30:2; 15:2, 9:3, 5:1) (I), compared with a compression:ventilation ratio of 3:1 (C), improve outcome (O)?

Outcomes:
PaCO2,Oxygenation,Surrogate marker(s) of perfusion,Hospital length of stay,Favorable neurologic outcome,Survival to Discharge

Prioritized Outcomes (1= most critical; final number = least important):

1. Favourable neurologic outcome

2. Survival to discharge

3. Hospital length of stay

4. Respiration (oxygenation and ventilation/PaCO2)

5. Surrogate markers of perfusion

Domain chairs: Manuel Boller

Evidence evaluators: Eunice Yuh, Kristen Hutchinson, final review by Manuel Boller

Conflicts of interest: None declared

Search strategy: See attached document

Evidence Review:

Study Design		Reduced Quality Factors 0 = no serious, - = serious, - - = very serious				Positive Quality Factors 0 = none, + = one, ++ = multiple			Dichotomous Outcome Summary			Non-Dichotomous Outcome Summary Brief description	Overall Quality High, moderate, low, very low, none
No of studies	Study Type	RoB	Indirectness	Imprecision	Inconsistency	Large Effect	Dose-Response	Confounder	# Intervention with Outcome	# Control with Outcome	RR (95% CI)
Outcome: Neurological outcome - No information in the SoF, 0 studies identified.
0	N/A												Non
Outcome: Survival to discharge.
3	ES	-	--	-	0	0	0	0	43/48	37/40	0.9685 (0.8498-1.1037), P=0.6310		Very low
Outcome: Hospital length of stay: - No information in the SoF, 0 studies identified.
0	N/A												None
Outcome: Surrogate markers of respiration
8	ES	-	--	-	0	0	0	0					Very low
Outcome: surrogate markers of perfusion
3	ES	-	--	-	0	0	0	0					Very low

PICO Question Summary

Introduction

Ventilation is of higher importance during resuscitation of transitional newborns than post-transitional newborns, pediatric or adult animals undergoing CPR, as the respiratory transition from fluid-filled to aerated lungs is a key process at birth and its failure is the main cause of cardiopulmonary arrest at the time of delivery.( Hooper 2018) Current guidelines in newborn infants, based on expert opinion, suggest administration of compressions and ventilation at a ratio of 3:1, given at a rate to allow 90 compressions and 30 breaths to be delivered per minute (i.e., 120 events per minute).( Wyckoff 2020) The interruption of chest compressions to deliver a breath is expected to optimize lung aeration when compared to concurrently administered ventilations and compressions, but this has not been conclusively evaluated (see NB-14). Moreover, in newborn puppies and kittens that are most often non-intubated during CPR, concurrent ventilations and compressions are not recommended due to the presumed lack of efficacy of breaths delivered during chest compressions in this setting and the risk for severe gastric insufflation, regurgitation and aspiration.(van Eijk 2024) A lower C:V ratio (e.g., 3:1) is generally expected to deliver more breaths per minute and favor ventilation, while a higher C:V ratio (e.g., 15:2) will lead to more compressions over time and favor circulation. We herein ask whether in newborn puppies and kittens undergoing CPR with compressions alternating with ventilations at a particular ratio (C:V ratio), resuscitators should target a C:V ratio of 3:1 as recommend for newborn infants, or whether another C:V ratio is preferrable.

Consensus on science

Outcome 1: Favorable neurologic outcome For the critical outcome of favorable neurologic outcome, we identified no studies addressing the question. Outcome 2: Survival to discharge For the next most critical outcome of survival to discharge, we identified 3 experimental neonatal piglet studies that addressed the question (very low quality of evidence, downgraded for serious risk of bias, very serious indirectness, and imprecision). (Solevag 2010/192, Solevag 2011/193, Pasquin 2018/204) All the studies involved post-transitional piglets of 12 - 96 hours of age in which asphyxial arrest was induced by a combination of a hypercarbic/hypoxic inspiratory gas mixture and endotracheal tube clamping. Resuscitation included a 30-second ventilation-only period followed by ventilation and chest compressions synchronized such that chest compressions were alternating with breaths at a certain ratio. Specifically, C:V ratios of 2:1, 4:1, 9:3 and 15:2 were compared to a C:V ratio of 3:1. No differences in survival to 4 hours after ROSC emerged between any of the C:V ratios examined. Pooled analysis showed no difference between those piglets resuscitated with a C:V ratio of 3:1 (n=40), compared to other C:V ratios (n=48) (RR=0.97, 95% CI 0.85-1.10, P=0.63). Outcome 3: Hospital length of stay For the important outcome of hospital length of stay, we identified no studies addressing the question. Outcome 4: Respiration (Oxygenation and Ventilation) For the important outcome of respiratory function, we identified 8 experimental studies that addressed the question (very low quality of evidence, downgraded for serious risk of bias, very serious indirectness, and imprecision), 4 of which included newborn piglets (Solevag 2010/192, Solevag 2011/193, Dannevig 2012/196, Pasquin 2018/204) and 4 were manikin studies.( Boldingh 2016/208, Hemaway 2013/602, Solevag 2012/601, Srikantan 2005) All piglet studies were again utilizing post-transitional piglets of 1 - 4 days of age that underwent asphyxial arrest, and all studies compared resuscitation with a C:V ratio of 3:1 with other compression to ventilation ratios, including 2:1, 4:1, 9:3 and 15:2. No significant differences were identified between 3:1 groups and any of the other groups in EtCO2 during resuscitation or PaCO2 or SpO2 values immediately after ROSC.( Solevag 2010/192, Solevag 2011/193, Pasquin 2018/204) Pasquin found that median tidal volumes were higher in the 2:1 group (27 mL, IQR 19-31), than the 4:1 group (14 mL, IQR 11-18; P=0.02) with intermediary values resulting from the 3:1 approach (22 mL, IQR 17-23).( Pasquin 2018/204) Dannevig et al. compared the effect of 3:1 versus 9:3 compression-to-ventilation ratios on markers of lung injury (e.g., TNF, ICAM-1 and MMP2/9), and found no differences between the studied C:V ratios.( Dannevig 2012/196) The 4 studies conducted in human newborn manikins indicate that the lower C:V ratio of 3:1, compared to 5:1, 9:3, 10:2 or 15:2 leads to higher minute ventilation (Boldingh 2016/208, Solevag 2012/601, Srikantan 2005) and tidal volume (Hemaway 2013/602, Solevag 2012/601, Srikantan 2005) and led to more effective breaths based on chest rise.( Srikantan 2005) Outcome 5: Surrogate markers of perfusion For the important outcome of surrogate markers of perfusion, we identified 3 experimental studies in newborn piglets that addressed the question (very low quality of evidence, downgraded for serious risk of bias, very serious indirectness, and imprecision) (Solevag 2010/192, Solevag 2011/193, Pasquin 2018/204). These studies were those already discussed previously, and hemodynamic outcomes (i.e., MAP, lactate) immediately after ROSC were comparable among different C:V groups in all studies.

Treatment recommendation

In newborn puppies and kittens receiving chest compressions and PPV, we suggest a C:V ratio of 4:1.(weak recommendation, expert opinion)

Justification of treatment recommendation

In making this recommendation, we acknowledge there is insufficient published information to arrive at an evidence-based recommendation for the preferred ventilation and compression strategy in newborn puppies and kittens requiring chest compressions. The committee considers intubation of the very small newborn dogs and cats not routinely feasible due to technical difficulties and the fact that often several newborns require attention concurrently. Without endotracheal intubation the delivery of PPV without concurrent compressions is highly important for breath efficacy, and effective ventilations are a higher priority in transitional newborns. The studies above suggested that lower C:V ratio will support higher TV and higher efficacy of breaths.( Hemaway 2013/602, Solevag 2012/601, Srikantan 2005, Pasquin 2018/204) However, lower C:V ratios will also lead to reduced chest compressions delivered by minute, which could be compromising blood flow and thus oxygen delivery to vital organs. To balance the need for a low C:V ratio to optimize ventilation with the need for an adequate number of compressions per minute, the committee suggests a C:V ratio of 4:1, while the chest compressions should be delivered at 150 compressions per minute. Mathematical modelling suggests that a higher compression rate than in adult dogs and cats is preferable in newborns (100 to 800 g bodyweight) (see NB12).( Babbs 2009) In addition, newborn puppies and kittens are markedly smaller than the piglets (> 2 kg bodyweight) included in the study by Pasquin and colleagues.( Pasquin 2018/204) Time required to deliver an adequate tidal volume is therefore shorter. With the recommended C:V ratio of 4:1, we suggest delivering 150 actions per minute, of which 120 consist in chest compressions and 30 consist in breaths. In other words, each 4:1 cycle is repeated 30 times over the course of a minute, each cycle taking approximately 2 seconds.

Knowledge gaps

There is a need to determine (1) whether one C:V ratio is better than another in newborn puppies and kittens; (2) whether rescuers can administer compressions at a rate of 150/min and how many breaths per minute are actually delivered with this strategy.

Related worksheet(s): NB-12: compression rates; NB-14: synchronous (CV) versus asynchronous ventilation

Additional references:

● Wyckoff MH, Wyllie J, Aziz K, de Almeida MF, Fabres J, Fawke J, Guinsburg R, Hosono S, Isayama T, Kapadia VS, Kim HS, Liley HG, McKinlay CJD, Mildenhall L, Perlman JM, Rabi Y, Roehr CC, Schmölzer GM, Szyld E, Trevisanuto D, Velaphi S, Weiner GM; Neonatal Life Support Collaborators.

● Babbs CF, Meyer A, Nadkarni V. Neonatal CPR: room at the top--a mathematical study of optimal chest compression frequency versus body size. Resuscitation. 2009 Nov;80(11):1280-4. doi: 10.1016/j.resuscitation.2009.07.014. Epub 2009 Aug 27. PMID: 19713026.

● van Eijk JA, Doeleman LC, Loer SA, Koster RW, van Schuppen H, Schober P. Ventilation during cardiopulmonary resuscitation: A narrative review. Resuscitation. 2024 Oct;203:110366. doi: 10.1016/j.resuscitation.2024.110366. Epub 2024 Aug 23. PMID: 39181499.

Hooper SB, Kitchen MJ, Polglase GR, Roehr CC, Te Pas AB. The physiology of neonatal resuscitation. Curr Opin Pediatr. 2018 Apr;30(2):187-191. doi: 10.1097/MOP.0000000000000590. PMID: 29373331.

Summary of relevant papers:

Solevag 2010: Extended series of cardiac compressions during CPR in a swine model of perinatal asphyxia.

● Population: Piglets, 12-36 hours old, anesthetized and PPV, asphyxiated with CO2 and reduction of FiO2 until HR 0, 20 s of asystole

● Outcomes: Primary outcome: Time to ROSC; further ROSC rate, inflammatory markers in BALF and CSF, MAP, survival to 4 hours

● Intervention: 3:1

● Comparator: 9:3

● #of subjects in each group: 16 piglets per group

● Results: No difference in Time to ROSC, ROSC rate, blood gases (PaCO2, SpO2) immediately after ROSC, no difference in lactate or inflammatory markers.

Solevag 2011: Return of spontaneous circulation with a compression:ventilation ratio of 15:2 versus 3:1 in newborn pigs with cardiac arrest due to asphyxia.

● Population: Newborn piglets, post transitionial at age 12-36 hours, weight 2+ kg; anesthesized; asphyxiated by reduction in FiO2, reduction in RR, and addition of CO2; until asystole; 20 s of asystole

● Outcomes: ROSC, Time to ROSC, MAP at ROSC, PCO2 at ROSC, SPO2 at ROSC, survival to 4 hours

● Intervention: PPV only for 30 seconds (PIP 25 cm H2O) then manual chest compressions with metronome (90 cpm) and CV:3;1; observation for 4 hours post ROSC

● Comparator: CV 15:2

● #of subjects in each group: 11 piglets

● Results: ROSC in 9/11 for both groups; Time to ROSC not different; No difference in PaCO2, or SpO2, overall no difference in any metrics examined.

Pasquin 2018: Comparison of Different Compression to Ventilation Ratios (2: 1, 3: 1, and 4: 1) during Cardiopulmonary Resuscitation in a Porcine Model of Neonatal Asphyxia.

● Population: Piglets, 1-4 days old, anesthetized, trached, asphyxiation by tube clamping until CPA, followed by PPV for 30secs

● Outcomes: Primary: Time to ROSC, Other: ROSC, Survival to 4 hours

● Intervention: 3:1

● Comparator: 2:1, 4:1

● #of subjects in each group: 8 animals per group, plus 7 in sham group

● Results: No difference in time to ROSC, ROSC, survival to 4 hours

Dannevig 2012: Lung Injury in Asphyxiated Newborn Pigs Resuscitated from Cardiac Arrest - The Impact of Supplementary Oxygen, Longer Ventilation Intervals and Chest Compressions at Different Compression-to-Ventilation RatiosNOTE THE CLINICAL DATA HEREIN HAS ALREADY BEEN REPORTED IN THE SOLEVAG 2010 AND 2011 PAPERS, SO CAN NOT DUPLICATE THE REPORTING. ONLY THE CSF DATA ARE NEW!

● Population: piglets, 12-36h of age, anesthetized, trach and PPV, asphyxiation by CO2 in inspiratory gas, until CPA

● Outcomes: qPCR for inflammatory mediators from BAL and lung tissue (collected 4 hours after ROSC)

● Intervention: (1) 3:1 after 30 secs of ventilation

● Comparator: ;(2) 3:1 after 60 seconds of ventilation; (3) 3:1 after 90 seconds of ventilation; (4) 9:3 after 30 second of PPV; (5) 3:1 after PPV with room air at 21, but then 3:1 with 100% O2;

● #of subjects in each group: 94 total, group size between 8 and 16

● Results: No difference in ROSC, time to ROSC between different rations, and no difference in markers of brain inflammation (hippocampus or cortex) between different C:V ratios.

●

Dannevig 2013: Brain inflammation induced by severe asphyxia in newborn pigs and the impact of alternative resuscitation strategies on the newborn central nervous system. NOTE THE CLINICAL DATA HEREIN HAS ALREADY BEEN REPORTED IN THE SOLEVAG 2010 AND 2011 PAPERS, SO CAN NOT DUPLICATE THE REPORTING. ONLY THE CSF DATA ARE NEW!

● Population: piglets, 24-34h of age, anesthetized, trach and PPV, asphyxiation by CO2 in inspiratory gas, until CPA

● Outcomes: ROSC, time to ROSC, MAP, PaCO2 immediately after ROSC; 4 hours after ROSC: S100, Gene expression for MMp-2, ICAM-1, IL-6, TNFalpha, caspase e, MMP-p in hippocampus and frontal cortex.

● Intervention: (1) 3:1 after 30 secs of ventilation

● Comparator: ;(2) 3:1 after 60 seconds of ventilation; (3) 3:1 after 90 seconds of ventilation; (4) 9:3 after 30 second of PPV; (5) 3:1 after PPV with room air at 21, but then 3:1 with 100% O2; C:15:2 after 30 secs of PPV with room air.

● #of subjects in each group: 94 total, group size between 8 and 16

● Results: No difference in ROSC, time to ROSC between different rations, and no difference in markers of brain inflammation (hippocampus or cortex) between different C:V ratios.

Simulation/Manikin studies

Boldingh AM, Solevåg A, Aasen E, et al. Resuscitators who compared four simulated infant cardiopulmonary resuscitation methods favoured the three-to-one compression-to-ventilation ratio. Acta paediatrica (Oslo, Norway : 1992) 2016;105:910–6.

● Population: Manikin study, randomized, crossover; newborn manikin

● Outcomes: Number, depth and rate of CC; number of breaths, TV and RR; secondary, compression depth decay; preference of rescuers

● Intervention: 3:1

● Comparator: 9:3, 15:2

● #of subjects in each group: 42 pairs of rescuers (MD, nurses, students)

● Results: No difference in CC depth; less ventilation rates; TV similar, MV reduced; overall comparable between 3:1 and 9:2, less ventilation in 15:2; 3:1 preferred as perceived as easiest to coordinate.

Hemway RJ, Christman C, Perlman J. The 3:1 is superior to a 15:2 ratio in a newborn manikin model in terms of quality of chest compressions and number of ventilations. Archives Dis Child - Fetal Neonatal Ed 2013;98:F42.

● Population: Newborn manikin study

● Outcomes: Depth of compressions, decay of compression depth over time, compression rates, and breaths per minute

● Intervention: 3:1

● Comparator: 5:1, 15:2

● #of subjects in each group: 32 physicians, nurses

● Results: greater depth in 3:1, compared to 15:2; no decay in 3:1, but for 5:1 and 15:2; highest breaths rate for 3:1, which is logic (30 bpm for 3:1, 20 bpm for 5:1 and 15 bpm for 15:2); higher compression rates in 5:1 and 15:2

Solevåg A, Madland JM, Gjærum E, et al. Minute ventilation at different compression to ventilation ratios, different ventilation rates, and continuous chest compressions with asynchronous ventilation in a newborn manikin. Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine 2012;20:73.

● Population: 2 newborn manikins, 2 rescuers performing CPR with T-Piece

● Outcomes: MV

● Intervention: CV 3:1; all given such the total events per minute were 120.

● Comparator: CV 9:3 (same breaths per minute as 3:1, 30 bpm), 15:2 (only 13-15 bpm)

● #of subjects in each group:

● Results: Lower MV in (9.3 and 15:2 versus 3:1; 9:3 (140 (134–144)) and 15:2 (77 (74–83)) as compared to 3:1 (191(183–199)) P<0.001; same was also true for the tidal volumes..

Srikantan SK, Srikantan SK, Berg RA, et al. Effect of one-rescuer compression/ventilation ratios on cardiopulmonary resuscitation in infant, pediatric, and adult manikins. Pediatric Critical Care Medicine 2005;6:293–7.

● Population: Maniking study, 35 healthcare providers delivering 5 min epochs of 1-rescuer CPR at VC ratios of 3:1, 5:1, 10:2 and 15:28, compressions 100 cpm; infant manikin

● Outcomes: Effective compressions and ventilations per minute, subjective fatigue, exertion

● Intervention: 3:1

● Comparator: 5:1, 10:2, 15:2

● #of subjects in each group:

● Results: Lower number of effective compressions per minute with 3:1 (57±14) compared to all other groups (5:1, 67±11; 10:2, 64±10; 15:2, 70±7), (P<0.05) but higher number of effective ventilations with 3:1 (19±4), compared to other groups (5:1, 13±2; 10:2, 13±2; 15:2, 9±1)